Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Although risk factors for this cancer have not been well characterized, cigarette smoking is implicated in approximately one quarter to one third of pancreatic cancers, and long-term smoking, (more than 20 years), doubles the risk. We hypothesize that DNA repair capacity influences risk for pancreatic cancer, and that polymorphisms in DNA repair and cell cycle genes modulate the efficiency of DNA repair capacity, and therefore influence an individual's risk of developing pancreatic cancer. In order to address these questions, we will conduct a case-control study of 400 pancreatic cancer cases and 400 cousin controls who will be identified by their respective relatives. We will determine if selected polymorphisms in nucleotide excision repair (NER) genes and cell cycle genes, either alone, or in combination with smoking status, influence risk for pancreatic cancer. The polymorphisms are ERCC1, XPC, XPD/ERCC2, XPA, XPG/ERCC5, XPB/ERCC3 and XPF/ERCC4 for the NER pathway, and cyclin D1, p16, p21 and p53 for the cell cycle genes. The NER pathway is involved in repair of DNA damage caused by smoking, while cell cycle control genes are important in cellular response to DNA damage caused by smoking. We will assess the DNA repair capacity phenotype using the host cell reactivation assay and the tobacco carcinogen, benzo[a]pyrene (BPDE) as the mutagen, on cases and cousin controls. A complementary assay, BPDE-induced DNA adduct assay will also be carried out on the cases and cousin controls. We will determine if polymorphisms in cell cycle genes or genes in the NER pathway modulate the DNA repair capacity phenotype or the BPDE-induced DNA adducts phenotype. This will be achieved by correlating these phenotypes with the genotypes in cases and controls separately. A second goal (in cases only) will be to evaluate genetic predictors of response to therapy. For this case series approach, we will enroll 250 cases from the total group of 400 patients whom we estimate will have received pre-operative treatment with gemcitabine and radiation. We will determine if DNA repair capacity, BPDE-induced DNA adduct levels, polymorphisms in DNA repair genes, and/or polymorphisms in cell cycle genes modulate response to this treatment. The proposed studies were designed to elucidate genetic factors that may modulate risk for development of sporadic pancreatic cancer as well as response to chemoradiotherapy, and will provide important information that may lead to new strategies for the prevention, early detection and treatment of the disease. The proposed studies may also help to determine which subset of patients is more likely to respond to combined preoperative treatment with gemcitabine and radiation.